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Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence

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Abstract

Studies reviewed here implicate the extended amygdala in the negative affective states and increased drug-seeking that occur during protracted abstinence from chronic drug exposure. Norepinephrine (NE) and corticotropin-releasing factor (CRF) signaling in the extended amygdala, including the bed nucleus of the stria terminalis, shell of the nucleus accumbens, and central nucleus of the amygdala, are generally involved in behavioral responses to environmental and internal stressors. Hyperactivity of stress response systems during addiction drives many negative components of drug abstinence. In particular, NE signaling from the nucleus tractus solitarius (NTS) to the extended amygdala, along with increased CRF transmission within the extended amygdala, are critical for the aversiveness of acute opiate withdrawal as well as stress-induced relapse of drug-seeking for opiates, cocaine, ethanol, and nicotine. NE and CRF transmission in the extended amygdala are also implicated in the increased anxiety that occurs during prolonged abstinence from chronic opiates, cocaine, ethanol, and cannabinoids. Many of these stress-associated behaviors are reversed by NE or CRF antagonists given systemically or locally within the extended amygdala. Finally, increased Fos activation in the extended amygdala and NTS is associated with the enhanced preference for drugs and decreased preference for natural rewards observed during protracted abstinence from opiates and cocaine, indicating that these areas are involved in the altered reward processing associated with addiction. Together, these findings suggest that involvement of the extended amygdala and its noradrenergic afferents in anxiety, stress-induced relapse, and altered reward processing reflects a common function for these circuits in stress modulation of drug-seeking.

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References

  • Ahmed SH, Walker JR, Koob GF (2000) Persistent increase in the motivation to take heroin in rats with a history of drug escalation. Neuropsychopharmacology 22:413–421. doi:10.1016/S0893-133X(99)00133-5

    PubMed  CAS  Google Scholar 

  • Akaoka H, Aston-Jones G (1991) Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input. J Neurosci 11:3830–3839

    PubMed  CAS  Google Scholar 

  • Alheid GF, Heimer L (1988) New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: the striatopallidal, amygdaloid, and corticopetal components of substantia innominata. Neuroscience 27:1–39. doi:10.1016/0306-4522(88)90217-5

    PubMed  CAS  Google Scholar 

  • Amit Z, Brown ZW (1982) Actions of drugs of abuse on brain reward systems: a reconsideration with specific attention to alcohol. Pharmacol Biochem Behav 17:233–238. doi:10.1016/0091-3057(82)90075-2

    PubMed  CAS  Google Scholar 

  • Amit Z, Brown ZW, Levitan DE, Ogren SO (1977) Noradrenergic mediation of the positive reinforcing properties of ethanol: I. Suppression of ethanol consumption in laboratory rats following dopamine-beta-hydroxylase inhibition. Arch Int Pharmacodyn Ther 230:65–75

    CAS  Google Scholar 

  • Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12. doi:10.1677/joe.0.1600001

    PubMed  CAS  Google Scholar 

  • Aston-Jones G, Harris GC (2004) Brain substrates for increased drug seeking during protracted withdrawal. Neuropharmacology 47(Suppl 1):167–179. doi:10.1016/j.neuropharm.2004.06.020

    PubMed  CAS  Google Scholar 

  • Aston-Jones G, Rajkowski J, Kubiak P, Akaoka H (1992) Acute morphine induces oscillatory discharge of noradrenergic locus coeruleus neurons in the waking monkey. Neurosci Lett 140:219–224

    Google Scholar 

  • Aston-Jones G, Shiekhattar R, Akaoka H, Rajkowski J, Kubiak P (1993) Opiates influence locus coeruleus neurons by potent indirect and direct actions. In: Hammer RP Jr (ed) The neurobiology of opiates. CRC Press, Boca Raton, FL, pp 175–202

    Google Scholar 

  • Aston-Jones G, Hirata H, Akaoka H (1997) Local opiate withdrawal in locus coeruleus in vivo. Brain Res 765:331–336. doi:10.1016/S0006-8993(97)00682-3

    PubMed  CAS  Google Scholar 

  • Aston-Jones G, Delfs JM, Druhan J, Zhu Y (1999) The bed nucleus of the stria terminalis. A target site for noradrenergic actions in opiate withdrawal. Ann N Y Acad Sci 877:486–498. doi:10.1111/j.1749-6632.1999.tb09284.x

    CAS  Google Scholar 

  • Aston-Jones G, Mejias-Aponte CA, Waterhouse B (2008) Norepinephrine: CNS Pathways, Neurophysiology. In: Squire L, Albright T, Bloom F, Gage F, Spitzer N (eds) The New Encyclopedia of Neuroscience. Elsevier, San Diego (in press)

  • Baldo BA, Daniel RA, Berridge CW, Kelley AE (2003) Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J Comp Neurol 464:220–237. doi:10.1002/cne.10783

    PubMed  Google Scholar 

  • Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557. doi:10.1146/annurev.pharmtox.44.101802.121410

    PubMed  CAS  Google Scholar 

  • Basso AM, Spina M, Rivier J, Vale W, Koob GF (1999) Corticotropin-releasing factor antagonist attenuates the “anxiogenic-like” effect in the defensive burying paradigm but not in the elevated plus-maze following chronic cocaine in rats. Psychopharmacology (Berl) 145:21–30. doi:10.1007/s002130051028

    CAS  Google Scholar 

  • Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42:33–84. doi:10.1016/S0165-0173(03)00143-7

    PubMed  Google Scholar 

  • Berridge CW, Stratford TL, Foote SL, Kelley AE (1997) Distribution of dopamine beta-hydroxylase-like immunoreactive fibers within the shell subregion of the nucleus accumbens. Synapse 27:230–241. doi:10.1002/(SICI)1098-2396(199711)27:3<230::AID-SYN8>3.0.CO;2-E

    PubMed  CAS  Google Scholar 

  • Bird SJ, Kuhar MJ (1977) Iontophoretic application of opiates to the locus coeruleus. Brain Res 122:523–533. doi:10.1016/0006-8993(77)90462-0

    PubMed  CAS  Google Scholar 

  • Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A (2006) Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 49:589–601. doi:10.1016/j.neuron.2006.01.016

    PubMed  CAS  Google Scholar 

  • Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF et al (2005) Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci USA 102:19168–19173. doi:10.1073/pnas.0507480102

    PubMed  CAS  Google Scholar 

  • Bremner JD, Krystal JH, Southwick SM, Charney DS (1996a) Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies. Synapse 23:28–38. doi:10.1002/(SICI)1098-2396(199605)23:1<28::AID-SYN4>3.0.CO;2-J

    CAS  Google Scholar 

  • Bremner JD, Krystal JH, Southwick SM, Charney DS (1996b) Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse 23:39–51. doi:10.1002/(SICI)1098-2396(199605)23:1<39::AID-SYN5>3.0.CO;2-I

    CAS  Google Scholar 

  • Britton KT, Svensson T, Schwartz J, Bloom FE, Koob GF (1984) Dorsal noradrenergic bundle lesions fail to alter opiate withdrawal or suppression of opiate withdrawal by clonidine. Life Sci 34:133–139. doi:10.1016/0024-3205(84)90583-6

    PubMed  CAS  Google Scholar 

  • Caille S, Espejo EF, Reneric JP, Cador M, Koob GF, Stinus L (1999) Total neurochemical lesion of noradrenergic neurons of the locus ceruleus does not alter either naloxone-precipitated or spontaneous opiate withdrawal nor does it influence ability of clonidine to reverse opiate withdrawal. J Pharmacol Exp Ther 290:881–892

    PubMed  CAS  Google Scholar 

  • Caine SB, Thomsen M, Gabriel KI, Berkowitz JS, Gold LH, Koob GF et al (2007) Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice. J Neurosci 27:13140–13150. doi:10.1523/JNEUROSCI.2284-07.2007

    PubMed  CAS  Google Scholar 

  • Carboni E, Silvagni A (2004) Dopamine reuptake by norepinephrine neurons: exception or rule? Crit Rev Neurobiol 16:121–128. doi:10.1615/CritRevNeurobiol.v16.i12.130

    PubMed  CAS  Google Scholar 

  • Carboni E, Silvagni A, Rolando MT, Di Chiara G (2000) Stimulation of in vivo dopamine transmission in the bed nucleus of stria terminalis by reinforcing drugs. J Neurosci 20:RC102

    Google Scholar 

  • Cecchi M, Khoshbouei H, Javors M, Morilak DA (2002a) Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuroscience 112:13–21. doi:10.1016/S0306-4522(02)00062-3

    PubMed  CAS  Google Scholar 

  • Cecchi M, Khoshbouei H, Morilak DA (2002b) Modulatory effects of norepinephrine, acting on alpha 1 receptors in the central nucleus of the amygdala, on behavioral and neuroendocrine responses to acute immobilization stress. Neuropharmacology 43:1139–1147. doi:10.1016/S0028-3908(02)00292-7

    PubMed  CAS  Google Scholar 

  • Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C et al (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451. doi:10.1016/S0092-8674(00)81973-X

    PubMed  CAS  Google Scholar 

  • Chieng B, Christie MJ (1995) Lesions to terminals of noradrenergic locus coeruleus neurones do not inhibit opiate withdrawal behaviour in rats. Neurosci Lett 186:37–40. doi:10.1016/0304-3940(95)11276-3

    PubMed  CAS  Google Scholar 

  • Childress AR, Ehrman R, McLellan AT, MacRae J, Natale M, O’Brien CP (1994) Can induced moods trigger drug-related responses in opiate abuse patients? J Subst Abuse Treat 11:17–23. doi:10.1016/0740-5472(94)90060-4

    PubMed  CAS  Google Scholar 

  • Christie MJ (1991) Mechanisms of opioid actions on neurons of the locus coeruleus. Prog Brain Res 88:197–205. doi:10.1016/S0079-6123(08)63809-1

    PubMed  CAS  Google Scholar 

  • Chu K, Koob GF, Cole M, Zorrilla EP, Roberts AJ (2007) Dependence-induced increases in ethanol self-administration in mice are blocked by the CRF1 receptor antagonist antalarmin and by CRF1 receptor knockout. Pharmacol Biochem Behav 86:813–821. doi:10.1016/j.pbb.2007.03.009

    PubMed  CAS  Google Scholar 

  • Clark MS, Kaiyala KJ (2003) Role of corticotropin-releasing factor family peptides and receptors in stress-related psychiatric disorders. Semin Clin Neuropsychiatry 8:119–136. doi:10.1053/scnp.2003.50011

    PubMed  Google Scholar 

  • Contarino A, Zanotti A, Drago F, Natolino F, Lipartiti M, Giusti P (1997) Conditioned place preference: no tolerance to the rewarding properties of morphine. Naunyn Schmiedebergs Arch Pharmacol 355:589–594. doi:10.1007/PL00004988

    PubMed  CAS  Google Scholar 

  • Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K et al (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 96:748–753. doi:10.1073/pnas.96.2.748

    PubMed  CAS  Google Scholar 

  • Davis M (1993) Pharmacological analysis of fear-potentiated startle. Braz J Med Biol Res 26:235–260

    PubMed  CAS  Google Scholar 

  • Davis M (2006) Neural systems involved in fear and anxiety measured with fear-potentiated startle. Am Psychol 61:741–756. doi:10.1037/0003-066X.61.8.741

    PubMed  Google Scholar 

  • de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE et al (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322–327. doi:10.1073/pnas.95.1.322

    PubMed  Google Scholar 

  • Delfs JM, Zhu Y, Druhan JP, Aston-Jones GS (1998) Origin of noradrenergic afferents to the shell subregion of the nucleus accumbens: anterograde and retrograde tract-tracing studies in the rat. Brain Res 806:127–140. doi:10.1016/S0006-8993(98)00672-6

    PubMed  CAS  Google Scholar 

  • Delfs JM, Zhu Y, Druhan JP, Aston-Jones G (2000) Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion. Nature 403:430–434. doi:10.1038/35000212

    PubMed  CAS  Google Scholar 

  • Di Chiara G (2002) Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behav Brain Res 137:75–114. doi:10.1016/S0166-4328(02)00286-3

    PubMed  CAS  Google Scholar 

  • Diana M, Pistis M, Muntoni A, Rossetti ZL, Gessa G (1992) Marked decrease of A10 dopamine neuronal firing during ethanol withdrawal syndrome in rats. Eur J Pharmacol 221:403–404. doi:10.1016/0014-2999(92)90734-L

    PubMed  CAS  Google Scholar 

  • Diana M, Pistis M, Carboni S, Gessa GL, Rossetti ZL (1993) Profound decrement of mesolimbic dopaminergic neuronal activity during ethanol withdrawal syndrome in rats: electrophysiological and biochemical evidence. Proc Natl Acad Sci USA 90:7966–7969. doi:10.1073/pnas.90.17.7966

    PubMed  CAS  Google Scholar 

  • Diana M, Pistis M, Muntoni A, Gessa G (1995) Profound decrease of mesolimbic dopaminergic neuronal activity in morphine withdrawn rats. J Pharmacol Exp Ther 272:781–785

    PubMed  CAS  Google Scholar 

  • Diana M, Pistis M, Muntoni A, Gessa G (1996) Mesolimbic dopaminergic reduction outlasts ethanol withdrawal syndrome: evidence of protracted abstinence. Neuroscience 71:411–415. doi:10.1016/0306-4522(95)00482-3

    PubMed  CAS  Google Scholar 

  • Diana M, Melis M, Muntoni AL, Gessa GL (1998) Mesolimbic dopaminergic decline after cannabinoid withdrawal. Proc Natl Acad Sci USA 95:10269–10273. doi:10.1073/pnas.95.17.10269

    PubMed  CAS  Google Scholar 

  • Diana M, Muntoni AL, Pistis M, Melis M, Gessa GL (1999) Lasting reduction in mesolimbic dopamine neuronal activity after morphine withdrawal. Eur J NeuroSci 11:1037–1041. doi:10.1046/j.1460-9568.1999.00488.x

    PubMed  CAS  Google Scholar 

  • Dumont EC, Williams JT (2004) Noradrenaline triggers GABAA inhibition of bed nucleus of the stria terminalis neurons projecting to the ventral tegmental area. J Neurosci 24:8198–8204. doi:10.1523/JNEUROSCI.0425-04.2004

    PubMed  CAS  Google Scholar 

  • Dunn AJ, Swiergiel AH (2008) The role of corticotropin-releasing factor and noradrenaline in stress-related responses, and the inter-relationships between the two systems. Eur J Pharmacol 583:186–193. doi:10.1016/j.ejphar.2007.11.069

    PubMed  CAS  Google Scholar 

  • Dunn AJ, Swiergiel AH, Palamarchouk V (2004) Brain circuits involved in corticotropin-releasing factor-norepinephrine interactions during stress. Ann N Y Acad Sci 1018:25–34. doi:10.1196/annals.1296.003

    PubMed  CAS  Google Scholar 

  • Egli RE, Kash TL, Choo K, Savchenko V, Matthews RT, Blakely RD et al (2005) Norepinephrine modulates glutamatergic transmission in the bed nucleus of the stria terminalis. Neuropsychopharmacology 30:657–668

    PubMed  CAS  Google Scholar 

  • Erb S, Stewart J (1999) A role for the bed nucleus of the stria terminalis, but not the amygdala, in the effects of corticotropin-releasing factor on stress-induced reinstatement of cocaine seeking. J Neurosci 19:RC35

    Google Scholar 

  • Erb S, Shaham Y, Stewart J (1998) The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats. J Neurosci 18:5529–5536

    PubMed  CAS  Google Scholar 

  • Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J (2000) Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology 23:138–150. doi:10.1016/S0893-133X(99)00158-X

    PubMed  CAS  Google Scholar 

  • Erb S, Salmaso N, Rodaros D, Stewart J (2001) A role for the CRF-containing pathway from central nucleus of the amygdala to bed nucleus of the stria terminalis in the stress-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 158:360–365. doi:10.1007/s002130000642

    CAS  Google Scholar 

  • Fibiger HC, Phillips AG (1986) Reward, motivation, cognition: psychobiology of mesotelencephalic dopamine systems. In: Mountcastle VB, Bloom FE, Geiger SR (eds) Handbook of physiology, Sect. 1: The nervous system, vol 4. American Physiological Society, Bethesda, MD, pp 647–675

    Google Scholar 

  • File SE (1990) New strategies in the search for anxiolytics. Drug Deliv 5:195–201

    CAS  Google Scholar 

  • Forray MI, Bustos G, Gysling K (1999) Noradrenaline inhibits glutamate release in the rat bed nucleus of the stria terminalis: in vivo microdialysis studies. J Neurosci Res 55:311–320. doi:10.1002/(SICI)1097-4547(19990201)55:3<311::AID-JNR6>3.0.CO;2-E

    PubMed  CAS  Google Scholar 

  • Fox HC, Talih M, Malison R, Anderson GM, Kreek MJ, Sinha R (2005) Frequency of recent cocaine and alcohol use affects drug craving and associated responses to stress and drug-related cues. Psychoneuroendocrinology 30:880–891. doi:10.1016/j.psyneuen.2005.05.002

    PubMed  CAS  Google Scholar 

  • Fox HC, Bergquist KL, Hong KI, Sinha R (2007) Stress-induced and alcohol cue-induced craving in recently abstinent alcohol-dependent individuals. Alcohol Clin Exp Res 31:395–403. doi:10.1111/j.1530-0277.2006.00320.x

    PubMed  Google Scholar 

  • Freedman LJ, Cassell MD (1994) Distribution of dopaminergic fibers in the central division of the extended amygdala of the rat. Brain Res 633:243–252. doi:10.1016/0006-8993(94)91545-8

    PubMed  CAS  Google Scholar 

  • Fuentealba JA, Forray MI, Gysling K (2000) Chronic morphine treatment and withdrawal increase extracellular levels of norepinephrine in the rat bed nucleus of the stria terminalis. J Neurochem 75:741–748. doi:10.1046/j.1471-4159.2000.0750741.x

    PubMed  CAS  Google Scholar 

  • Funk CK, O’Dell LE, Crawford EF, Koob GF (2006) Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J Neurosci 26:11324–11332. doi:10.1523/JNEUROSCI.3096-06.2006

    PubMed  CAS  Google Scholar 

  • Funk CK, Zorrilla EP, Lee MJ, Rice KC, Koob GF (2007) Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biol Psychiatry 61:78–86. doi:10.1016/j.biopsych.2006.03.063

    PubMed  CAS  Google Scholar 

  • Georges F, Aston-Jones G (2001) Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis. J Neurosci 21:RC160

    Google Scholar 

  • Georges F, Aston-Jones G (2002) Activation of ventral tegmental area cells by the bed nucleus of the stria terminalis: a novel excitatory amino acid input to midbrain dopamine neurons. J Neurosci 22:5173–5187

    PubMed  CAS  Google Scholar 

  • Georges F, Aston-Jones G (2003) Prolonged activation of mesolimbic dopaminergic neurons by morphine withdrawal following clonidine: participation of imidazoline and norepinephrine receptors. Neuropsychopharmacology 28:1140–1149

    PubMed  CAS  Google Scholar 

  • Georgescu D, Zachariou V, Barrot M, Mieda M, Willie JT, Eisch AJ et al (2003) Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci 23:3106–3111

    PubMed  CAS  Google Scholar 

  • Gewirtz JC, McNish KA, Davis M (1998) Lesions of the bed nucleus of the stria terminalis block sensitization of the acoustic startle reflex produced by repeated stress, but not fear-potentiated startle. Prog Neuropsychopharmacol Biol Psychiatry 22:625–648. doi:10.1016/S0278-5846(98)00028-1

    PubMed  CAS  Google Scholar 

  • Goeders NE (1997) A neuroendocrine role in cocaine reinforcement. Psychoneuroendocrinology 22:237–259. doi:10.1016/S0306-4530(97)00027-9

    PubMed  CAS  Google Scholar 

  • Goeders NE (2003) The impact of stress on addiction. Eur Neuropsychopharmacol 13:435–441. doi:10.1016/j.euroneuro.2003.08.004

    PubMed  Google Scholar 

  • Gold MS, Redmond DE Jr, Kleber HD (1978) Clonidine blocks acute opiate-withdrawal symptoms. Lancet 2:599–602. doi:10.1016/S0140-6736(78)92823-4

    PubMed  CAS  Google Scholar 

  • Gracy KN, Dankiewicz LA, Koob GF (2001) Opiate withdrawal-induced fos immunoreactivity in the rat extended amygdala parallels the development of conditioned place aversion. Neuropsychopharmacology 24:152–160. doi:10.1016/S0893-133X(00)00186-X

    PubMed  CAS  Google Scholar 

  • Hamlin AS, Buller KM, Day TA, Osborne PB (2004) Effect of naloxone-precipitated morphine withdrawal on c-fos expression in rat corticotropin-releasing hormone neurons in the paraventricular hypothalamus and extended amygdala. Neurosci Lett 362:39–43. doi:10.1016/j.neulet.2004.02.033

    PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (1993a) Beta-adrenergic antagonists attenuate somatic and aversive signs of opiate withdrawal. Neuropsychopharmacology 9:303–311

    PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (1993b) Beta-adrenergic antagonists attenuate withdrawal anxiety in cocaine- and morphine-dependent rats. Psychopharmacology (Berl) 113:131–136. doi:10.1007/BF02244345

    CAS  Google Scholar 

  • Harris GC, Aston-Jones G (1994) Involvement of D2 dopamine receptors in the nucleus accumbens in the opiate withdrawal syndrome. Nature 371:155–157. doi:10.1038/371155a0

    PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (2001) Augmented accumbal serotonin levels decrease the preference for a morphine associated environment during withdrawal. Neuropsychopharmacology 24:75–85. doi:10.1016/S0893-133X(00)00184-6

    PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (2003a) Altered motivation and learning following opiate withdrawal: evidence for prolonged dysregulation of reward processing. Neuropsychopharmacology 28:865–871. doi:10.1038/sj.npp.1300122

    PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (2003b) Enhanced morphine preference following prolonged abstinence: association with increased Fos expression in the extended amygdala. Neuropsychopharmacology 28:292–299. doi:10.1038/sj.npp.1300037

    PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (2006) Arousal and reward: a dichotomy in orexin function. Trends Neurosci 29:571–577. doi:10.1016/j.tins.2006.08.002

    PubMed  CAS  Google Scholar 

  • Harris GC, Aston-Jones G (2007) Activation in extended amygdala corresponds to altered hedonic processing during protracted morphine withdrawal. Behav Brain Res 176:251–258. doi:10.1016/j.bbr.2006.10.012

    PubMed  CAS  Google Scholar 

  • Harris GC, Altomare K, Aston-Jones G (2001) Preference for a cocaine-associated environment is attenuated by augmented accumbal serotonin in cocaine withdrawn rats. Psychopharmacology (Berl) 156:14–22. doi:10.1007/s002130100693

    CAS  Google Scholar 

  • Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556–559. doi:10.1038/nature04071

    PubMed  CAS  Google Scholar 

  • Harris GC, Hummel M, Wimmer M, Mague SD, Aston-Jones G (2007) Elevations of FosB in the nucleus accumbens during forced cocaine abstinence correlate with divergent changes in reward function. Neuroscience 147:583–591. doi:10.1016/j.neuroscience.2007.04.050

    PubMed  CAS  Google Scholar 

  • Heimer L, Zahm DS, Churchill L, Kalivas PW, Wohltmann C (1991) Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience 41:89–125. doi:10.1016/0306-4522(91)90202-Y

    PubMed  CAS  Google Scholar 

  • Heimer L, Alheid GF, Zahm DS (1993) Basal forebrain organization: An anatomical framework for motor aspects of drive and motivation. In: Kalivas PW, Barnes CD (eds) Limbic Motor Circuits and Neuropsychiatry. CRC Press, Boca Raton, pp 1–43

    Google Scholar 

  • Heinrichs SC, Koob GF (2004) Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J Pharmacol Exp Ther 311:427–440. doi:10.1124/jpet.103.052092

    PubMed  CAS  Google Scholar 

  • Heinrichs SC, Menzaghi F, Schulteis G, Koob GF, Stinus L (1995) Suppression of corticotropin-releasing factor in the amygdala attenuates aversive consequences of morphine withdrawal. Behav Pharmacol 6:74–80. doi:10.1097/00008877-199501000-00011

    PubMed  CAS  Google Scholar 

  • Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA (2001) Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103:777–797. doi:10.1016/S0306-4522(01)00033-1

    PubMed  CAS  Google Scholar 

  • Hnasko TS, Sotak BN, Palmiter RD (2005) Morphine reward in dopamine-deficient mice. Nature 438:854–857. doi:10.1038/nature04172

    PubMed  CAS  Google Scholar 

  • Hnasko TS, Sotak BN, Palmiter RD (2007) Cocaine-conditioned place preference by dopamine-deficient mice is mediated by serotonin. J Neurosci 27:12484–12488. doi:10.1523/JNEUROSCI.3133-07.2007

    PubMed  CAS  Google Scholar 

  • Hornby PJ, Piekut DT (1989) Opiocortin and catecholamine input to CRF-immunoreactive neurons in rat forebrain. Peptides 10:1139–1146. doi:10.1016/0196-9781(89)90005-3

    PubMed  CAS  Google Scholar 

  • Hyman SM, Fox H, Hong KI, Doebrick C, Sinha R (2007) Stress and drug-cue-induced craving in opioid-dependent individuals in naltrexone treatment. Exp Clin Psychopharmacol 15:134–143. doi:10.1037/1064-1297.15.2.134

    PubMed  CAS  Google Scholar 

  • Ivanov A, Aston-Jones G (2001) Local opiate withdrawal in locus coeruleus neurons in vitro. J Neurophysiol 85:2388–2397

    PubMed  CAS  Google Scholar 

  • Jasmin L, Narasaiah M, Tien D (2006) Noradrenaline is necessary for the hedonic properties of addictive drugs. Vascul Pharmacol 45:243–250. doi:10.1016/j.vph.2005.08.030

    PubMed  CAS  Google Scholar 

  • Kayaba Y, Nakamura A, Kasuya Y, Ohuchi T, Yanagisawa M, Komuro I et al (2003) Attenuated defense response and low basal blood pressure in orexin knockout mice. Am J Physiol Regul Integr Comp Physiol 285:R581–R593

    PubMed  Google Scholar 

  • Koob GF (1999a) Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry 46:1167–1180. doi:10.1016/S0006-3223(99)00164-X

    PubMed  CAS  Google Scholar 

  • Koob GF (1999b) The role of the striatopallidal and extended amygdala systems in drug addiction. Ann N Y Acad Sci 877:445–460. doi:10.1111/j.1749-6632.1999.tb09282.x

    PubMed  CAS  Google Scholar 

  • Koob GF (1999c) Stress, corticotropin-releasing factor, and drug addiction. Ann N Y Acad Sci 897:27–45. doi:10.1111/j.1749-6632.1999.tb07876.x

    PubMed  CAS  Google Scholar 

  • Koob GF (2003) Neuroadaptive mechanisms of addiction: studies on the extended amygdala. Eur Neuropsychopharmacol 13:442–452. doi:10.1016/j.euroneuro.2003.08.005

    PubMed  CAS  Google Scholar 

  • Koob GF, Heinrichs SC (1999) A role for corticotropin releasing factor and urocortin in behavioral responses to stressors. Brain Res 848:141–152. doi:10.1016/S0006-8993(99)01991-5

    PubMed  CAS  Google Scholar 

  • Koob G, Kreek MJ (2007) Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 164:1149–1159. doi:10.1176/appi.ajp.2007.05030503

    PubMed  Google Scholar 

  • Koob GF, Robledo P, Markou A, Caine SB (1993) The mesocorticolimbic circuit in drug dependence and reward–a role for the extended amygdala? In: Kalivas PW, Barnes CD (eds) Limbic motor circuits and neuropsychiatry. CRC Press, Boca Raton, pp 289–309

    Google Scholar 

  • Korf J, Bunney BS, Aghajanian GK (1974) Noradrenergic neurons: morphine inhibition of spontaneous activity. Eur J Pharmacol 25:165–169. doi:10.1016/0014-2999(74)90045-4

    PubMed  CAS  Google Scholar 

  • Kosten TA (1994) Clonidine attenuates conditioned aversion produced by naloxone-precipitated opiate withdrawal. Eur J Pharmacol 254:59–63. doi:10.1016/0014-2999(94)90370-0

    PubMed  CAS  Google Scholar 

  • Kosten TR, Rounsaville BJ, Kleber HD (1986) A 2.5-year follow-up of depression, life crises, and treatment effects on abstinence among opioid addicts. Arch Gen Psychiatry 43:733–738

    PubMed  CAS  Google Scholar 

  • Laviolette SR, Nader K, van der Kooy D (2002) Motivational state determines the functional role of the mesolimbic dopamine system in the mediation of opiate reward processes. Behav Brain Res 129:17–29. doi:10.1016/S0166-4328(01)00327-8

    PubMed  CAS  Google Scholar 

  • Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B (2006) The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 148:752–759. doi:10.1038/sj.bjp.0706789

    PubMed  CAS  Google Scholar 

  • Le AD, Harding S, Juzytsch W, Watchus J, Shalev U, Shaham Y (2000) The role of corticotrophin-releasing factor in stress-induced relapse to alcohol-seeking behavior in rats. Psychopharmacology (Berl) 150:317–324. doi:10.1007/s002130000411

    CAS  Google Scholar 

  • Le AD, Harding S, Juzytsch W, Funk D, Shaham Y (2005) Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology (Berl) 179:366–373. doi:10.1007/s00213-004-2036-y

    CAS  Google Scholar 

  • Lee Y, Davis M (1997) Role of the hippocampus, the bed nucleus of the stria terminalis, and the amygdala in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex. J Neurosci 17:6434–6446

    PubMed  CAS  Google Scholar 

  • Leri F, Flores J, Rodaros D, Stewart J (2002) Blockade of stress-induced but not cocaine-induced reinstatement by infusion of noradrenergic antagonists into the bed nucleus of the stria terminalis or the central nucleus of the amygdala. J Neurosci 22:5713–5718

    PubMed  CAS  Google Scholar 

  • Lett BT (1989) Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacology (Berl) 98:357–362. doi:10.1007/BF00451687

    CAS  Google Scholar 

  • Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X et al (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365–376. doi:10.1016/S0092-8674(00)81965-0

    PubMed  CAS  Google Scholar 

  • Liu X, Weiss F (2002) Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J Neurosci 22:7856–7861

    PubMed  CAS  Google Scholar 

  • Lu L, Ceng X, Huang M (2000) Corticotropin-releasing factor receptor type I mediates stress-induced relapse to opiate dependence in rats. NeuroReport 11:2373–2378

    Article  PubMed  CAS  Google Scholar 

  • Lu L, Shepard JD, Scott Hall F, Shaham Y (2003) Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review. Neurosci Biobehav Rev 27:457–491. doi:10.1016/S0149-7634(03)00073-3

    PubMed  CAS  Google Scholar 

  • Lu L, Chen H, Su W, Ge X, Yue W, Su F et al (2005) Role of withdrawal in reinstatement of morphine-conditioned place preference. Psychopharmacology (Berl) 181:90–100. doi:10.1007/s00213-005-2207-5

    CAS  Google Scholar 

  • Maldonado R (1997) Participation of noradrenergic pathways in the expression of opiate withdrawal: biochemical and pharmacological evidence. Neurosci Biobehav Rev 21:91–104. doi:10.1016/0149-7634(95)00061-5

    PubMed  CAS  Google Scholar 

  • Mantsch JR, Baker DA, Francis DM, Katz ES, Hoks MA, Serge JP (2008) Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration by rats. Psychopharmacology (Berl) 195:591–603. doi:10.1007/s00213-007-0950-5

    CAS  Google Scholar 

  • Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M et al (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25. doi:10.1002/cne.1190

    PubMed  CAS  Google Scholar 

  • Mason ST, Corcoran ME, Fibiger HC (1979) Noradrenaline and ethanol intake in the rat. Neurosci Lett 12:137–142. doi:10.1016/0304-3940(79)91494-0

    PubMed  CAS  Google Scholar 

  • Mateo Y, Lack CM, Morgan D, Roberts DC, Jones SR (2005) Reduced dopamine terminal function and insensitivity to cocaine following cocaine binge self-administration and deprivation. Neuropsychopharmacology 30:1455–1463. doi:10.1038/sj.npp.1300687

    PubMed  CAS  Google Scholar 

  • McClung CA, Ulery PG, Perrotti LI, Zachariou V, Berton O, Nestler EJ (2004) DeltaFosB: a molecular switch for long-term adaptation in the brain. Brain Res Mol Brain Res 132:146–154. doi:10.1016/j.molbrainres.2004.05.014

    PubMed  CAS  Google Scholar 

  • McFarland K, Davidge SB, Lapish CC, Kalivas PW (2004) Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. J Neurosci 24:1551–1560. doi:10.1523/JNEUROSCI.4177-03.2004

    PubMed  CAS  Google Scholar 

  • Merlo Pich E, Lorang M, Yeganeh M, Rodriguez de Fonseca F, Raber J, Koob GF et al (1995) Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 15:5439–5447

    PubMed  CAS  Google Scholar 

  • Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, Ma S et al (2005) Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry 29:1214–1224. doi:10.1016/j.pnpbp.2005.08.007

    PubMed  CAS  Google Scholar 

  • Nader K, van der Kooy D (1996) Clonidine antagonizes the aversive effects of opiate withdrawal and the rewarding effects of morphine only in opiate withdrawn rats. Behav Neurosci 110:389–400. doi:10.1037/0735-7044.110.2.389

    PubMed  CAS  Google Scholar 

  • Nakagawa T, Yamamoto R, Fujio M, Suzuki Y, Minami M, Satoh M et al (2005) Involvement of the bed nucleus of the stria terminalis activated by the central nucleus of the amygdala in the negative affective component of morphine withdrawal in rats. Neuroscience 134:9–19. doi:10.1016/j.neuroscience.2005.03.029

    PubMed  CAS  Google Scholar 

  • Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827:243–260. doi:10.1016/S0006-8993(99)01336-0

    PubMed  CAS  Google Scholar 

  • Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, Miyatake M et al (2006) Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 26:398–405. doi:10.1523/JNEUROSCI.2761-05.2006

    PubMed  CAS  Google Scholar 

  • Newman-Tancredi A, Audinot-Bouchez V, Gobert A, Millan MJ (1997) Noradrenaline and adrenaline are high affinity agonists at dopamine D4 receptors. Eur J Pharmacol 319:379–383. doi:10.1016/S0014-2999(96)00985-5

    PubMed  CAS  Google Scholar 

  • Nishino S (2007) Narcolepsy: pathophysiology and pharmacology. J Clin Psychiatry 68(Suppl 13):9–15

    PubMed  CAS  Google Scholar 

  • Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355:39–40. doi:10.1016/S0140-6736(99)05582-8

    PubMed  CAS  Google Scholar 

  • O’Brien CP (1997) A range of research-based pharmacotherapies for addiction. Science 278:66–70. doi:10.1126/science.278.5335.66

    PubMed  CAS  Google Scholar 

  • Olson VG, Heusner CL, Bland RJ, During MJ, Weinshenker D, Palmiter RD (2006) Role of noradrenergic signaling by the nucleus tractus solitarius in mediating opiate reward. Science 311:1017–1020. doi:10.1126/science.1119311

    PubMed  CAS  Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167. doi:10.1016/0165-0270(85)90031-7

    PubMed  CAS  Google Scholar 

  • Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG et al (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015

    PubMed  CAS  Google Scholar 

  • Phelix CF, Liposits Z, Paull WK (1992) Monoamine innervation of bed nucleus of stria terminalis: an electron microscopic investigation. Brain Res Bull 28:949–965. doi:10.1016/0361-9230(92)90218-M

    PubMed  CAS  Google Scholar 

  • Phelix CF, Liposits Z, Paull WK (1994) Catecholamine-CRF synaptic interaction in a septal bed nucleus: afferents of neurons in the bed nucleus of the stria terminalis. Brain Res Bull 33:109–119. doi:10.1016/0361-9230(94)90056-6

    PubMed  CAS  Google Scholar 

  • Phelps EA, LeDoux JE (2005) Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48:175–187. doi:10.1016/j.neuron.2005.09.025

    PubMed  CAS  Google Scholar 

  • Piazza PV, Le Moal ML (1996) Pathophysiological basis of vulnerability to drug abuse: role of an interaction between stress, glucocorticoids, and dopaminergic neurons. Annu Rev Pharmacol Toxicol 36:359–378. doi:10.1146/annurev.pa.36.040196.002043

    PubMed  CAS  Google Scholar 

  • Pothos E, Rada P, Mark GP, Hoebel BG (1991) Dopamine microdialysis in the nucleus accumbens during acute and chronic morphine, naloxone-precipitated withdrawal and clonidine treatment. Brain Res 566:348–350. doi:10.1016/0006-8993(91)91724-F

    PubMed  CAS  Google Scholar 

  • Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33. doi:10.1016/S0014-2999(03)01272-X

    PubMed  CAS  Google Scholar 

  • Rasmussen K, Beitner-Johnson DB, Krystal JH, Aghajanian GK, Nestler EJ (1990) Opiate withdrawal and the rat locus coeruleus: behavioral, electrophysiological, and biochemical correlates. J Neurosci 10:2308–2317

    PubMed  CAS  Google Scholar 

  • Rasmussen DD, Mitton DR, Green J, Puchalski S (2001) Chronic daily ethanol and withdrawal: 2. Behavioral changes during prolonged abstinence. Alcohol Clin Exp Res 25:999–1005. doi:10.1111/j.1530-0277.2001.tb02308.x

    CAS  Google Scholar 

  • Rassnick S, Heinrichs SC, Britton KT, Koob GF (1993a) Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal. Brain Res 605:25–32. doi:10.1016/0006-8993(93)91352-S

    PubMed  CAS  Google Scholar 

  • Rassnick S, Stinus L, Koob GF (1993b) The effects of 6-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat. Brain Res 623:16–24. doi:10.1016/0006-8993(93)90004-7

    PubMed  CAS  Google Scholar 

  • Richter RM, Weiss F (1999) In vivo CRF release in rat amygdala is increased during cocaine withdrawal in self-administering rats. Synapse 32:254–261

    PubMed  CAS  Google Scholar 

  • Risbrough VB, Stein MB (2006) Role of corticotropin releasing factor in anxiety disorders: a translational research perspective. Horm Behav 50:550–561. doi:10.1016/j.yhbeh.2006.06.019

    PubMed  CAS  Google Scholar 

  • Rodaros D, Caruana DA, Amir S, Stewart J (2007) Corticotropin-releasing factor projections from limbic forebrain and paraventricular nucleus of the hypothalamus to the region of the ventral tegmental area. Neuroscience 150:8–13. doi:10.1016/j.neuroscience.2007.09.043

    PubMed  CAS  Google Scholar 

  • Rodgers RJ (1997) Animal models of ‘anxiety’: where next? Behav Pharmacol 8:477–496; discussion 497–504. doi:10.1097/00008877-199711000-00003

    Google Scholar 

  • Rodriguez de Fonseca F, Carrera MR, Navarro M, Koob GF, Weiss F (1997) Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science 276:2050–2054. doi:10.1126/science.276.5321.2050

    PubMed  CAS  Google Scholar 

  • Rossetti ZL, Melis F, Carboni S, Diana M, Gessa GL (1992) Alcohol withdrawal in rats is associated with a marked fall in extraneuronal dopamine. Alcohol Clin Exp Res 16:529–532. doi:10.1111/j.1530-0277.1992.tb01411.x

    PubMed  CAS  Google Scholar 

  • Sakamoto F, Yamada S, Ueta Y (2004) Centrally administered orexin-A activates corticotropin-releasing factor-containing neurons in the hypothalamic paraventricular nucleus and central amygdaloid nucleus of rats: possible involvement of central orexins on stress-activated central CRF neurons. Regul Pept 118:183–191. doi:10.1016/j.regpep.2003.12.014

    PubMed  CAS  Google Scholar 

  • Sakanaka M, Shibasaki T, Lederis K (1986) Distribution and efferent projections of corticotropin-releasing factor-like immunoreactivity in the rat amygdaloid complex. Brain Res 382:213–238. doi:10.1016/0006-8993(86)91332-6

    PubMed  CAS  Google Scholar 

  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585. doi:10.1016/S0092-8674(00)80949-6

    PubMed  CAS  Google Scholar 

  • Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y et al (2005) Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46:297–308. doi:10.1016/j.neuron.2005.03.010

    PubMed  CAS  Google Scholar 

  • Sarnyai Z, Biro E, Gardi J, Vecsernyes M, Julesz J, Telegdy G (1995) Brain corticotropin-releasing factor mediates ‘anxiety-like’ behavior induced by cocaine withdrawal in rats. Brain Res 675:89–97. doi:10.1016/0006-8993(95)00043-P

    PubMed  CAS  Google Scholar 

  • Sarnyai Z, Shaham Y, Heinrichs SC (2001) The role of corticotropin-releasing factor in drug addiction. Pharmacol Rev 53:209–243

    PubMed  CAS  Google Scholar 

  • Schank JR, Ventura R, Puglisi-Allegra S, Alcaro A, Cole CD, Liles LC et al (2006) Dopamine beta-hydroxylase knockout mice have alterations in dopamine signaling and are hypersensitive to cocaine. Neuropsychopharmacology 31:2221–2230

    PubMed  CAS  Google Scholar 

  • Shaham Y, Stewart J (1995) Stress reinstates heroin-seeking in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacology (Berl) 119:334–341. doi:10.1007/BF02246300

    CAS  Google Scholar 

  • Shaham Y, Rajabi H, Stewart J (1996) Relapse to heroin-seeking in rats under opioid maintenance: the effects of stress, heroin priming, and withdrawal. J Neurosci 16:1957–1963

    PubMed  CAS  Google Scholar 

  • Shaham Y, Funk D, Erb S, Brown TJ, Walker CD, Stewart J (1997) Corticotropin-releasing factor, but not corticosterone, is involved in stress-induced relapse to heroin-seeking in rats. J Neurosci 17:2605–2614

    PubMed  CAS  Google Scholar 

  • Shaham Y, Erb S, Leung S, Buczek Y, Stewart J (1998) CP-154, 526, a selective, non-peptide antagonist of the corticotropin-releasing factor1 receptor attenuates stress-induced relapse to drug seeking in cocaine- and heroin-trained rats. Psychopharmacology (Berl) 137:184–190. doi:10.1007/s002130050608

    CAS  Google Scholar 

  • Shaham Y, Erb S, Stewart J (2000a) Stress-induced relapse to heroin and cocaine seeking in rats: a review. Brain Res Brain Res Rev 33:13–33. doi:10.1016/S0165-0173(00)00024-2

    PubMed  CAS  Google Scholar 

  • Shaham Y, Highfield D, Delfs J, Leung S, Stewart J (2000b) Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons. Eur J NeuroSci 12:292–302. doi:10.1046/j.1460-9568.2000.00899.x

    PubMed  CAS  Google Scholar 

  • Shaham Y, Shalev U, Lu L, De Wit H, Stewart J (2003) The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168:3–20. doi:10.1007/s00213-002-1224-x

    CAS  Google Scholar 

  • Shalev U, Morales M, Hope B, Yap J, Shaham Y (2001) Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats. Psychopharmacology (Berl) 156:98–107. doi:10.1007/s002130100748

    CAS  Google Scholar 

  • Shippenberg TS, Heidbreder C (1995) Sensitization to the conditioned rewarding effects of cocaine: pharmacological and temporal characteristics. J Pharmacol Exp Ther 273:808–815

    PubMed  CAS  Google Scholar 

  • Siegel JM (2004) Hypocretin (orexin): role in normal behavior and neuropathology. Annu Rev Psychol 55:125–148. doi:10.1146/annurev.psych.55.090902.141545

    PubMed  Google Scholar 

  • Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 158:343–359. doi:10.1007/s002130100917

    CAS  Google Scholar 

  • Sinha R (2007) The role of stress in addiction relapse. Curr Psychiatry Rep 9:388–395. doi:10.1007/s11920-007-0050-6

    PubMed  Google Scholar 

  • Sinha R, Catapano D, O’Malley S (1999) Stress-induced craving and stress response in cocaine dependent individuals. Psychopharmacology (Berl) 142:343–351. doi:10.1007/s002130050898

    CAS  Google Scholar 

  • Sinha R, Talih M, Malison R, Cooney N, Anderson GM, Kreek MJ (2003) Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states. Psychopharmacology (Berl) 170:62–72. doi:10.1007/s00213-003-1525-8

    CAS  Google Scholar 

  • Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ (2006) Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatry 63:324–331. doi:10.1001/archpsyc.63.3.324

    PubMed  Google Scholar 

  • Smith RJ, Harris GC, Aston-Jones G (2004) Dependence prior to, but not subsequent to, stimulus-drug conditioning increases drug seeking during protracted morphine withdrawal. Program No. 576.13. 2004 Abstract Viewer and Itinerary Planner. Online. Society for Neuroscience, San Diego, CA

    Google Scholar 

  • Southwick SM, Bremner JD, Rasmusson A, Morgan CA 3rd, Arnsten A, Charney DS (1999) Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry 46:1192–1204. doi:10.1016/S0006-3223(99)00219-X

    PubMed  CAS  Google Scholar 

  • Spanagel R, Almeida OF, Bartl C, Shippenberg TS (1994) Endogenous kappa-opioid systems in opiate withdrawal: role in aversion and accompanying changes in mesolimbic dopamine release. Psychopharmacology (Berl) 115:121–127. doi:10.1007/BF02244761

    CAS  Google Scholar 

  • Specio SE, Wee S, O’Dell LE, Boutrel B, Zorrilla EP, Koob GF (2007) CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats. Psychopharmacology (Berl). doi:10.1007/s00213-007-0983-9

  • Stinus L, Cador M, Zorrilla EP, Koob GF (2005) Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal-induced conditioned place aversion in rats. Neuropsychopharmacology 30:90–98. doi:10.1038/sj.npp.1300487

    PubMed  CAS  Google Scholar 

  • Stornetta RL, Norton FE, Guyenet PG (1993) Autonomic areas of rat brain exhibit increased Fos-like immunoreactivity during opiate withdrawal in rats. Brain Res 624:19–28. doi:10.1016/0006-8993(93)90055-R

    PubMed  CAS  Google Scholar 

  • Strawn JR, Geracioti TD Jr (2008) Noradrenergic dysfunction and the psychopharmacology of posttraumatic stress disorder. Depress Anxiety 25:260–271. doi:10.1002/da.20292

    PubMed  CAS  Google Scholar 

  • Sutcliffe JG, de Lecea L (2002) The hypocretins: setting the arousal threshold. Nat Rev Neurosci 3:339–349. doi:10.1038/nrn808

    PubMed  CAS  Google Scholar 

  • Swiergiel AH, Takahashi LK, Kalin NH (1993) Attenuation of stress-induced behavior by antagonism of corticotropin-releasing factor receptors in the central amygdala in the rat. Brain Res 623:229–234. doi:10.1016/0006-8993(93)91432-R

    PubMed  CAS  Google Scholar 

  • Treit D, Pinel JP, Fibiger HC (1981) Conditioned defensive burying: a new paradigm for the study of anxiolytic agents. Pharmacol Biochem Behav 15:619–626. doi:10.1016/0091-3057(81)90219-7

    PubMed  CAS  Google Scholar 

  • Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438:71–75. doi:10.1016/S0014-5793(98)01266-6

    PubMed  CAS  Google Scholar 

  • Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP et al (2002) Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: regulation by corticotropin-releasing factor. Alcohol Clin Exp Res 26:1494–1501

    PubMed  CAS  Google Scholar 

  • Valdez GR, Zorrilla EP, Roberts AJ, Koob GF (2003) Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence. Alcohol 29:55–60. doi:10.1016/S0741-8329(03)00020-X

    PubMed  CAS  Google Scholar 

  • Veinante P, Stoeckel ME, Lasbennes F, Freund-Mercier MJ (2003) c-Fos and peptide immunoreactivities in the central extended amygdala of morphine-dependent rats after naloxone-precipitated withdrawal. Eur J NeuroSci 18:1295–1305. doi:10.1046/j.1460-9568.2003.02837.x

    PubMed  Google Scholar 

  • Walker DL, Davis M (1997) Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear. J Neurosci 17:9375–9383

    PubMed  CAS  Google Scholar 

  • Walker DL, Toufexis DJ, Davis M (2003) Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur J Pharmacol 463:199–216. doi:10.1016/S0014-2999(03)01282-2

    PubMed  CAS  Google Scholar 

  • Walters CL, Aston-Jones G, Druhan JP (2000) Expression of fos-related antigens in the nucleus accumbens during opiate withdrawal and their attenuation by a D2 dopamine receptor agonist. Neuropsychopharmacology 23:307–315. doi:10.1016/S0893-133X(00)00113-5

    PubMed  CAS  Google Scholar 

  • Wang X, Cen X, Lu L (2001) Noradrenaline in the bed nucleus of the stria terminalis is critical for stress-induced reactivation of morphine-conditioned place preference in rats. Eur J Pharmacol 432:153–161. doi:10.1016/S0014-2999(01)01487-X

    PubMed  CAS  Google Scholar 

  • Wang B, Shaham Y, Zitzman D, Azari S, Wise RA, You ZB (2005) Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J Neurosci 25:5389–5396. doi:10.1523/JNEUROSCI.0955-05.2005

    PubMed  CAS  Google Scholar 

  • Wang J, Fang Q, Liu Z, Lu L (2006) Region-specific effects of brain corticotropin-releasing factor receptor type 1 blockade on footshock-stress- or drug-priming-induced reinstatement of morphine conditioned place preference in rats. Psychopharmacology (Berl) 185:19–28. doi:10.1007/s00213-005-0262-6

    CAS  Google Scholar 

  • Wang B, You ZB, Rice KC, Wise RA (2007) Stress-induced relapse to cocaine seeking: roles for the CRF(2) receptor and CRF-binding protein in the ventral tegmental area of the rat. Psychopharmacology (Berl) 193:283–294. doi:10.1007/s00213-007-0782-3

    CAS  Google Scholar 

  • Watanabe T, Nakagawa T, Yamamoto R, Maeda A, Minami M, Satoh M (2003) Involvement of noradrenergic system within the central nucleus of the amygdala in naloxone-precipitated morphine withdrawal-induced conditioned place aversion in rats. Psychopharmacology (Berl) 170:80–88. doi:10.1007/s00213-003-1504-0

    CAS  Google Scholar 

  • Weinshenker D, Schroeder JP (2007) There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology 32:1433–1451. doi:10.1038/sj.npp.1301263

    PubMed  CAS  Google Scholar 

  • Weinshenker D, Rust NC, Miller NS, Palmiter RD (2000) Ethanol-associated behaviors of mice lacking norepinephrine. J Neurosci 20:3157–3164

    PubMed  CAS  Google Scholar 

  • Weiss F, Ciccocioppo R, Parsons LH, Katner S, Liu X, Zorrilla EP et al (2001) Compulsive drug-seeking behavior and relapse. Neuroadaptation, stress, and conditioning factors. Ann N Y Acad Sci 937:1–26

    PubMed  CAS  Google Scholar 

  • Willie JT, Chemelli RM, Sinton CM, Yanagisawa M (2001) To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 24:429–458. doi:10.1146/annurev.neuro.24.1.429

    PubMed  CAS  Google Scholar 

  • Winsky-Sommerer R, Yamanaka A, Diano S, Borok E, Roberts AJ, Sakurai T et al (2004) Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci 24:11439–11448. doi:10.1523/JNEUROSCI.3459-04.2004

    PubMed  CAS  Google Scholar 

  • Wise RA (1978) Catecholamine theories of reward: a critical review. Brain Res 152:215–247. doi:10.1016/0006-8993(78)90253-6

    PubMed  CAS  Google Scholar 

  • Wise RA (1996) Neurobiology of addiction. Curr Opin Neurobiol 6:243–251. doi:10.1016/S0959-4388(96)80079-1

    PubMed  CAS  Google Scholar 

  • Wise RA (2004) Dopamine, learning and motivation. Nat Rev Neurosci 5:483–494. doi:10.1038/nrn1406

    PubMed  CAS  Google Scholar 

  • Yoshida K, McCormack S, Espana RA, Crocker A, Scammell TE (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494:845–861. doi:10.1002/cne.20859

    PubMed  Google Scholar 

  • Zhou Y, Bendor J, Hofmann L, Randesi M, Ho A, Kreek MJ (2006) Mu opioid receptor and orexin/hypocretin mRNA levels in the lateral hypothalamus and striatum are enhanced by morphine withdrawal. J Endocrinol 191:137–145. doi:10.1677/joe.1.06960

    PubMed  CAS  Google Scholar 

  • Zislis G, Desai TV, Prado M, Shah HP, Bruijnzeel AW (2007) Effects of the CRF receptor antagonist d-Phe CRF((12–41)) and the alpha2-adrenergic receptor agonist clonidine on stress-induced reinstatement of nicotine-seeking behavior in rats. Neuropharmacology 53:958–966

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Gary Aston-Jones.

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Smith, R.J., Aston-Jones, G. Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence. Brain Struct Funct 213, 43–61 (2008). https://doi.org/10.1007/s00429-008-0191-3

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